Regenerative processes are poorly understood. This proposal aims to expand scientific understanding of how regeneration occurs in vertebrate limbs. In urodele amphibians, regeneration of a lost limb is thought to occur by dedifferentiation of remaining tissues to create a blastema, followed by cell proliferation and patterning events that direct the redifferentiation of cells to create components of the new limb. In Aim 1 of this proposal, individual cell lineages within a regenerating axolotl limb will be traced to determine the source of cells used for dedifferentiation and the fate of these cells within the new limb. The potential contribution of stem cells to limb regeneration in mammals will be explored in Aim 2. In mammals, limb regeneration is restricted to digit tips and becomes increasingly restricted distally with age. Aim 2 will test the hypothesis that a specific set of stem cells, msxl-expressing cells, found at the digit tips confers regenerative ability. Testing this hypothesis will involve transplanting msxl cells to more proximal locations and determining if they can induce regeneration there. If so, can the cells be manipulated to allow regeneration of proximal elements? [unreadable] [unreadable] [unreadable]